Vitamin D deficiency is highly prevalent in older people in the absence of vitamin D supplementation. The limited data available show marked inter-individual variability in response to vitamin D supplementation in very old, frail elderly wih almost 25% remaining vitamin D deficient (25-OH D < 20 ng/mL) when receiving the currently recommended 800 IU/day vitamin D. This proposal is for exploratory research on the use of a wide range of oral vitamin D3 doses in frail elderly living in controlled living environments. We will determine the dose response relationship of total and unbound 25- OH vitamin D3 to supplemental vitamin D3 at daily doses of 800 (currently recommended for the elderly), 2000, and 4000 IU or 50,000 IU/weekly in a randomized blinded investigation We will also compare the efficacy of each dosing regimen in achieving 25-OH vitamin D levels >20 ng/mL (50 nmol/L) and identify covariates that contribute to inter-individual variation in the dose response relationship. In patients with osteoporosis, relationships between unbound vs. total 25-OH on intact parathyroid hormone and a marker of bone resorption (beta-Ctx) will be analyzed. We will also examine responses of inflammatory cytokines. A long-term goal is to develop algorithms for estimation of D3 dosages to achieve target 25-OH vitamin D doses for very elderly and frail individuals. PUBLIC HEALTH RELEVANCE: Vitamin D deficiency is very common in the elderly but the dose required to normalize vitamin D levels has not been determined for very old or frail people. This proposal will evaluate responses to a wide range of daily oral vitamin D3 doses and a higher weekly dose of oral vitamin D3 in old, very old, frail, and nursing home patients to determine the best dose to correct vitamin D deficiency in the almost 2 million elderly Americans living in nursing homes. It will also explore what doses of vitamin D decrease inflammation and bone resorption.